SK120693A3 - Iodinated wetting agents - Google Patents

Abstract

Compounds having the structure (Z &rparstr& -COO-L-CO2M wherein (Z &rparstr& -COO is the residue of an iodinated aromatic acid; M is H, a cation, &lparstr& CH2CH2O &rparstr& mH, and &lparstr& CH2CH(OH)O &rparstr& pH; m is an integer from 1 to 150; p is an integer from 1 to 50; and L is one or more divalent linking groups selected from alkylene, cycloalkylene, arylene, arylenealkylene, and alkylenearylene are particularly useful as wetting agents in x-ray imaging compositions and in methods for x-ray diagnostic imaging.

Description

BACKGROUND OF THE INVENTION

X-ray imaging is a well known and extremely valuable measure for the early detection and diagnosis of various disease states in the human body. The use of contrast agents for image enhancement in medical X-ray imaging procedures is widespread. An excellent summary of iodinated and other contrast media for medical imaging is provided by D. P. Swanson et al. in Pharmaceuticals in Medical Imaging, 1990, MacMillan Publishing Company.

Published European patent application no. No. 0 498 4S2A discloses nanoparticular X-ray contrast media which have been shown to be particularly suitable for medical imaging. The particles consist of a sparingly soluble diagnostic composition that is adsorbed on a crosslinked surface tension modifier. These particles have a mean particle size of less than about 400 nm.

The present invention is directed to novel iodinated surfactants which are useful as surface tension modifiers in nanoparticle-based compositions.

SUMMARY OF THE INVENTION

Novel iodinated aromatic compounds have been produced which have been found to be particularly advantageous as wetting agents in contrast agents for X-ray radiation.

This particularly relates to compounds of the structure represented by the general formula I (Z) -COO-L-COsM (I)

wherein (Z) COO is a residue of iodinated aromatic acid

M represents a hydrogen atom, a cation, a group of the formula CH ₂ CHnO 1 NH or CCH ₂ CH (OH) O p H, m being an integer from 1 to 150,

P is an integer from 1 to 50 and

L 'is one or more divalent bonding groups from an alkylene, cycloalkylene, arylene, arylene-alkylene and alkylenarylene group.

An advantageous feature of the present invention is that the iodinated wettable compositions provide X-ray contrast agents whose agents contribute to enhancing the contrast.

Another advantageous feature is that the wetting compositions of the invention can be used in vivo to alter the interaction of particles with the reticuloendothelial system and thus allow the particles to be retained in the bloodstream or directed to specific organs.

Yet another advantageous feature is that the use of the wetting agents of the present invention can result in very small particles, for example having a size less than about 100 nm, which manifests both in a particular biodistribution, i.e. by passive targeting of the malignant tumor, and enhancing pharmaceutical stability. .

Preferred embodiments are described below.

In particular, the compounds of the invention are described herein in connection with their preferred use, i.e., as wetting agents for particular contrast agents, for X-ray imaging. However, it is believed that the compounds are equally suitable as wetting agents for therapeutic compositions and for various other applications.

In Structural Formula I above, (Z) COO means a residue of an iodinated aromatic acid. The iodinated aromatic acid may contain one, two, three or more iodine atoms per molecule. Preferred species contain at least two, and more preferably at least three iodine atoms per molecule. The iodinated compounds may contain substituents that do not have a detrimental effect on the compound's ability to enhance the contrast.

The acids include: acid acid acid seine acid acid acid iodipamide tractive examples of diatrizoic, metrizoic, urokonic, iotalamic, trimesic, ioxagalic (hexabrix) iowitalamic, tetrajiodterephthalic and the like.

suitable aromatic acids

In preferred embodiments, (Z) COO is a substituted triiodobenzoic acid residue which is substituted with acyl, carbamyl and / or acylamino.

In a particularly preferred embodiment, Z represents a group of the formula

wherein the number is 1, 2 or each of the substituents

R is, independently of one another, a hydrogen atom, an alkyl group having 1 to 18 carbon atoms or a fluoroalkyl group having 1 to 18 carbon atoms,

R ¹ and R ² are each independently hydrogen or C 1 -C 18 alkyl,

M represents a hydrogen atom or an alkali metal Ba - ¹ - or an ammonium cation, such as a soil, such as a cation, as the alkali metal cation is Na +, K +, Li +, Ca ++, NHa ⁺ , tetramethyl ammonium and the like; Wherein the integer is from 1 to 150 and represents an integer from 1 to 50 and represents one or more divalent linking groups, preferably selected from an alkylene group containing from 1 to 20 carbon atoms, preferably from 1 to 20 carbon atoms. 8 carbon atoms such as methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene and the like; arylene groups, preferably containing from 6 to 10 carbon atoms such as phenylene and naphthylene, arylene alkyl groups, the arylene and alkylene moieties of which are described above, and alkylene arylene groups, wherein the alkylene and arylene moieties are described above.

The alkylene, cycloalkylene, arylene, arylene-alkylene and alkylene-arylene groups of formula (I) above may be unsubstituted or may be substituted with various substituents that do not adversely affect the stability or efficacy of the compounds. Suitable substituents include alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, alkoxy, hydroxy, aryloxy, acyloxy, halogen, acylamino, carbalkoxy, carbamyl, and the like. However, reactive substituents are not preferred on the carbon atoms adjacent to the ester group.

The compounds of the invention may be prepared by reacting a carboxylate of an iodinated aromatic acid or a salt thereof, such as a sodium salt, with a functionalized acid of the formula:

X-L-COaM in which

X stands for

L and M are suitable

The cleavable meanings of said solvent.

group and above.

Suitable leaving groups include halogen such as bromine, chlorine and iodine, and sulfonyloxy such as methanesulfonyloxy and toluenesulfonyloxy. The carboxylates of iodinated aromatic acids and functionalized acids used as starting materials in the manufacture of the compounds of this invention are known compounds and / or can be prepared by techniques known in the art. For example, suitable acids include commercially available bromoacids and chloroacids

The general reaction scheme is as follows:

Z-COO ^- + L-CO2M --------- I

The reaction may be carried out at various temperatures ranging from -73 to 100 ° C, preferably from -40 to 50 ° C.

Preferably, the reaction may be carried out at room temperature, but higher or lower pressures may be contemplated.

In another embodiment, compounds of the invention wherein Μ represents a hydrogen atom or a cation can be produced by a two-step synthesis. First, the iodinated aromatic acid carboxylate can be reacted with a functionalized ester as described by Bacon et al. U.S. Pat. No. 07/990 987 entitled Iodinated Aroyloxy Esters, or Singh et al. U.S. Pat. 07/990 306 entitled Iodinated Aromatic Compounds. Then, the ester can be converted to the corresponding acid or its salt by hydrolysis using a technique well known in the art.

The following are particular illustrative examples of preferred compounds of the present invention that have been produced:

ä) 5-C / 3 ', 5'-bis (acetylamino) -2', 4 ', 6'-triiodophenyl 1 / carbonyloxy 3 pentanoic acid,

(b) 6-C / 3 ', 5'-bis (acetylamino) -2', 4 ', 6'-triiodophenates1 / 1oxy 3 hexanoic acid carbones,

(c) 7-C / 3 ', 5'-bis (acetylamino) -2', 4 ', 6'-triiodophenyl1 / carbonyloxy3heptanoic acid,

(d) 8-C / 3 ', 5'-bis (acetylamino) -2', 4 ', 6'-triiodophenyl / carbonyloxy-3-octanoic acid and,

(e) 4-C / 3 ', 5' -bis (acetylamino) -2 ', 4', 6'-triiodophenyl1 / carbonyloxymethyl 13-benzoic acids,

Preferred compounds of the invention represented by the general formula (I) above, wherein Z is a residue of diatrizoic acid and M is a hydrogen atom, are summarized below:

compound

a) (CH ₂ ) Λ b) (CH ₂₎ e c) (CH ₂ ) _a d) (CH ₂ ) ₇ e) —LH2 - CaHa -.

When used as a wetting agent in an X-ray contrast composition, the compound of the invention may contain up to about 40% by weight of iodine or more.

In preferred embodiments, the compounds of the invention may be incorporated as a wetting agent into particulate X-ray contrast media, preferably as modifiers in nanoparticulate X-ray contrast media, as described in published European Patent Application Ser. 0 498,482. Such nanoparticulate compositions can be produced by dispersing a sparingly soluble X-ray contrast agent in a liquid dispersing medium and wet grinding the agent in the presence of a solid grinding cartridge and a surface tension modifier to form nanoparticles. According to another embodiment, the wetting agent may be contacted with the contrast agent after attrition.

The relative amount of particulate x-ray contrast agent and wetting agent may vary widely, and the optimum amount of wetting agent may, for example, depend upon the particulate contrast agent and the selected wetting agent, the hydrophilic lipophilic equilibrium of the wetting agent, its solubility in water, the surface tension of aqueous solutions. composition and the like. The wetting agent may be present in an amount of from 0.1 to 90% by weight, preferably from 1 to 75% by weight, more preferably from about 1% to about 20% by weight of the total combined dry matter of the particulate contrast agent and the wetting agent.

up to 50 7. mass25 7. mass,

The X-ray contrast compositions of the present invention comprise the compounds described above, preferably as a wetting agent for the particulate contrast agent and a physiologically acceptable carrier therefor. For example, the particles may be dispersed in an aqueous liquid that serves as a carrier for the X-ray contrast agent. Other suitable carriers include liquid carriers such as mixtures of aqueous and non-aqueous solvents such as alcohols, gels, gases such as air, and powders.

The X-ray contrast composition may comprise from about 1 to 99.9% by weight, preferably from 2 to 45% by weight, and most preferably from 10 to 25% by weight of the above-described substance, the remainder of the composition being a carrier. , additives and the like. Compositions containing up to about 100% by weight of particles are contemplated when the composition is in lyophilized form.

The dose of the contrast agent to be administered may be selected according to a technique known to one skilled in the art such that a sufficient enhancement of the contrast effect is achieved. Typical dosages may range from 50 to 350 mg of iodine per kilogram of patient's body weight for a variety of imaging applications. For certain uses, for example for lymphography, lower doses, for example from 0.5 to 20 mg of iodine per kilogram, may be effective.

The X-ray contrast composition may comprise one or more conventional additives used to control and / or improve the properties of the X-ray contrast agent. For example, thickeners such as dextran or human serum albumin, buffers, viscosity control agents, suspending agents, anti-clotting agents, may be used.

and so on. Partial Tonicity Agents, Mixing Agents, Other Active Agents The inventory of certain particular ingredients includes dextran, human serum albumin, gelatin, dextrin, pectin, and sodium carboxycellulose. surfactants, gum preservatives, sugars such as sodium alginate, agar,

Such additives, etc., may be incorporated into the compositions of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The invention will now be illustrated by the following examples, which are in no way intended to limit the invention.

Example 1

Method of production. . 4-C / 3,, 5 ’-bis (acetylenes 1 and min) -2,, 4,, 6 - - triiodophenyl1 / carbonyloxymethyl1benzoic acid (R = L = -CH2-C6H4-, M = H)

CH ₃ , R 1

H, n

A mixture of 11.3 g (15.2 mmol) of 4- (ethoxycarbonyl) phenyl-C3,5bis (acetylamino) -2,4,6-triiodo-benzoate produced by the reaction of sodium di-diisoate and ethyl (4-bromomethyl-benzoate) as described by Singh et al. , cit. above, and 0.8 g (20.0 mmol) of sodium hydroxide are stirred and refluxed for 5 hours. The methanol was evaporated under reduced pressure and the remaining solution was filtered to remove some insoluble solids. The filtrate was acidified with concentrated hydrochloric acid to precipitate a white solid. The precipitate is collected, washed with water and dried under reduced pressure at 80-85 ° C. 9.8 g of a white solid are thus obtained in the form of granules, m.p. 289-292 ° C (dec.). CI-MS: MH + 749. 1 H-NMR spectral data (300 MHz) were consistent with the proposed structure of the compound.

Analysis for C19HIEE3 N2O6:

Calculated: C 30.51 7, H 2.02 7, I 50.89 X, N 3.74 7,

Found: C 30.35 7, H 1.91 7, I 51.05 7, N 3.62 7.

Example 2

Method for producing 6-C / 3 ', 5'-bis (acetylamino) -2', 4 ', 6'-triiodophenyl1 / carbonyloxy3hexanoic acid (R = CH-, R * = R2 = H, n = 3,

L = (CH ₂ ) s, M = H)

A mixture of 5.6 g (7.3 mmol) of bis (acetylamino) -2,4,6-triiodobenzoate ester,

Bacon et al., Loc. above, and 1.6 g (24.1 mmol) of 95 7 powdered potassium hydroxide in 25 mL of water are heated in a steam bath for 15 minutes. After cooling, the resulting solution was filtered and acidified with glacial acetic acid. The precipitate thus formed is washed with a 1: 1 solution of ethanol in ethyl ether and dried. There was thus obtained a crude product with a yield of 93% of theory. Recrystallization from dimethylformamide gave an analytically pure compound having a melting point of 251-255 ° C, CI-MS: MH + 729. 1 H-NMR spectral data (300 MHz) were consistent with the proposed structure.

6-ethoxy-6-oxohexyl-C3,5- produced as described

Analysis for Ci7 Hi <? I3 N2 O *:

Calculated Found:

C 28.05 Z, C 28.05 Z,

H 2.63 Z, I 52.29 Z, H 2.63 Z, I 52.39 Z,

N 3.85 Z, N 3.78 Z.

Example 3

X - ray nanoparticle wetting agent containing

6-C / 3 ', 5' -bis (acetyl amino) -2 ', 4', 6'-triiodophenyl / carbonyloxy-3-hexanoic acid is mixed with 6-ethanoic acid in concentrations ranging from 0.5 to 3 Z 6-Oxo-1-C3,5-bis (acetylamino) -2,4,6-tri iodophenylbenzoate and also with water sufficient to prepare a 10 Z suspension of the triiodo benzoate. All are ground for 7 days, the particle size being reduced to approximately 110 to 130 nm as determined by standard light scattering techniques.

Example 4

X - ray nanoparticle wetting agent containing

4-L / 3 ', 5'-Bis (acetylamino) -2', 4 ', 6'-tri-iodophenyl / carbonyloxymethyl-13-benzoic acid is treated as described above together with 6-ethoxy-6-oxohexyl-1- C3, 5-bis (acetylamino) -2,4,6-tri-iodophenylbenzoate, and particles with an average particle size of less than 110 nm are obtained, as determined by standard light scattering techniques.

Industrial usability

The method of diagnostic imaging for use in the medical procedures of the invention consists in administering to the body of the subject in need of such imaging, the above-described X-ray contrast in an amount producing an effective X-ray contrast. In addition to the human patient, the patient to be examined may be another mammalian species such as rabbits, dogs, cats, monkeys, sheep, pigs, horses, cattle and the like. Thereafter, at least a portion of the body containing the administered contrast agent is exposed to X-rays to produce a characteristic X-ray image that responds to the presence of the contrast agent. The image can then be visualized. For example, a visualization technique for X-ray radiation, preferably a high-contrast technique such as computed tomography, can be used in a conventional manner. In another embodiment, the characteristic imaging can be observed directly by combining a X-ray sensitive phosphor screen and a silver halide photographic film.

The compositions of the invention may be administered by different routes depending on the type of procedure and the anatomical orientation of the tissue to be examined. Suitable routes of administration are intravascular (arterial or venous), gavage, intravenous injection, rectal administration, subcutaneous administration, intramuscular administration, injection site administration, intrathecal administration, intracisternal administration or oral administration, administration by inhalation, administration by inhalation, cavities such as arthrography and the like.

In addition to preferred applications, for example imaging of the bloodstream, liver, spleen and lymph nodes, the X-ray contrast compositions of the present invention are unexpectedly suitable as well as contrast agents for any organ or body cavity. For example, the compositions of the present invention are particularly useful as angiographic, urographic, myelographic, gastrointestinal, cholecystographic and cholangiographic artrographic, hysterosalpingographic, oral and bronchographic contrast media.

Claims (7)

PATENT CLAIMS A compound of the structure represented by the general formula I (Z) -COO-L-CO 2 M (I), wherein (Z) COO represents a residue of iodinated aromatic acid M represents a hydrogen atom, a cation, a group of the formula (CHaCH5O1mH or CCH3CH (OH) OZ1pH), m represents an integer from 1 to 150, P is an integer from 1 to 50 and L represents one or more divalent linking groups from the alkylene, cycloalkylene, arylene, arylene, alkylene and alkylenenarylene groups. The compound of claim 1, wherein Z (COO) is a residue of an iodinated aromatic acid selected from of diatrizoic of metrizoic acids urokonic of iothalamic of trimesic kyse1iny ioxagalic of ioxitalamic of tetrajode terephthalate and iodipamide. The compound of claim 1, wherein Z (C00) is a diatrizoic acid residue j. - 13 A compound according to claim 1, which is selected from the group consisting of (a) 5-Γ / 3,, 5--bis (acetylamino) -2,, 4,, 6--triiodophenyl1 / 1-oxycarbone 3 pentanoic acid, b) acid-O-L '/ 3', 5 ^1-bis (acety1amino) -2 ', 4', O 'trijódfenny1 / karbonyloxy3 hexanoic acid, c) acid 7-C / ¹ 3 ', 5'-bis (acetylamino) -2', 4 ', 6'-trijódfeny1 / carbonyloxy 3 heptanoic, (d) 8-C / 3 ', 5'-bis (acetylamino) -2', 4 ', 6'-triiodophenyl1 / carbonyloxy 3-octanoic acid, and e) acid, 4-C / 3 ^1, 5 &apos; -bis <acetylamino) -2 ', 4', 6'-trijódíeny1 / 13 1oxymety carbonyl benzoic acid, The compound of claim 1, wherein Z is a group of the formula wherein n is 1, 2 or 3, each of the substituents R is, independently of one another, a hydrogen atom, an alkyl group having 1 to 18 carbon atoms or a fluoroalkyl group having 1 to 18 carbon atoms, R ¹ and R 2 are each independently hydrogen or C 1 -C 18 alkyl, 6. An X-ray contrast composition comprising a compound according to any one of the preceding claims. 7. An X-ray contrast composition further comprising a pharmaceutically acceptable carrier. A method of medical diagnostic X-ray imaging, characterized in that a contrasting effective amount of X-ray contrast agent is administered into the body of the mammal according to any one of claims 6 and 7.